Chiral lithium enolates

In a pioneering investigation on the addition of the following chiral lithium enolate to propanal, only poor substrate-induced diastereoselectivity (57 43) was obtained54-35. 

The chiral lithium enolate 2 reacts with symmetrical ketones to produce /(,/i-dialkyl-/l-hydroxy-acyl complexes 3 which serve as precursors to oc,/1-unsaturated iron complexes (see Section 1.3.4.2.5.1.1.). 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

The aldol condensations of the chiral lithium enolate 132 have been demonstrated to exhibit excellent erythro diastereoselection as... 

Reaction of the chiral lithium enolate of meso-2,6-dimethylcyclohexanone (6), generated by deprotonation with (R)-l-phenylethylamine and (/ )-camphor/(R)-l-phenylethylaniine derived chiral lithium amides (Table 1, entries 17 and 64) with 3-bromopropene, leads to homoallyl ketones of opposite absolute configuration in acceptable yield with poor to modest enantiomeric excess14, which can be determined directly by H-NMR spectroscopy in the presence of tris [3-(heptafluorohydroxymethylene)-D-camphorato]europium(III) [Eu(hfc)3]. 

SCHEME 31. Generation of a chiral lithium enolate by diastereocontrolled conjugate addition of an achiral nucleophile on a chiral substrate, followed by intramolecular alkylation146... 

On the other hand, the condensation of Gamer s aldehyde574 with the non-chiral lithium enolate of diethylacetamide in non-chelating conditions occurs preferentially on the 57-face with a moderate 37% d.e. The same reaction using the enolate of (R.R)- or (5,5)-pseudoephedrine acetamides resulted in identical anti aldol adducts, but with an amplification of the face recognition of the aldehyde for the matched (R, W )-pscudoephedrine (d.e. = 96%). On the other hand, the mismatched (5,5)-pseudoephedrine gave only 12% d.e. (Scheme 120)575. 

Synthesis of Unnatural (S)-Proline Derivatives. The condensation of pivaladehyde with (S)-proline yields stereoselec-tively, after lithiation and reaction with an electrophile, the hi-cyclic compound (28), which is a versatile educt for the synthesis of many a-suhstituted proline analogs (29) (eq 12). The reactions proceed via the formation of a chiral lithium enolate without the use of a chiral auxiliary (self-reproduction of chirality). The reaction with a variety of electrophiles cis to the t-Bu group yields a plethora of a-substituted (5)-proline derivatives (29). A limitation of this strategy is the acetal cleavage of some substituted products (28). ... 

Chiral boron enolates are effective in enantioselective aldol condensations, a transition-state model being proposed for the moderate chirality transfer exhibited (Scheme 57). ° Diastereoselection with chiral lithium enolates has also been demonstrated by a highly stereoselective synthesis of the Prelog-Djerassi lactonic acid. ... 

A significant improvement - as far as chiral lithium enolates of acetyl iron complexes are concerned - came from the complex 78, which carries a (pentafiuorophenyl)diphenylphosphane ligand instead of the usual tri-phenylphosphane. Thus, the enolate 79, generated by treatment with LDA, gives the diastereomeric adducts 80a and 80b in a diastereomeric ratio of 98.5 1.5 on treatment with benzaldehyde. A donor-acceptor interaction between the enolate oxygen atom and the fiuorinated aromatic ring, supported... 

In addition to this example of acyclic stereocontrol, the concept has also been applied to the cyclic chiral lithium enolate 101 this also resulted in high diastereoselectivity when the enantiomeric enolates were combined with the chiral aldehydes 102. As demonstrated by Eqs. (45) and (46), here again the stereochemical outcome is determined by the configuration of the enolate 101 [176]. 

Scheme 2.22 Enantioselective formation of axially chiral lithium enolate 80.

Compared to the aldol addition, the stereochemical scheme is complicated by the fact that the Michael acceptor may not always and not exclusively adopt the -configuration as shown in 421 but also as Z-diastereomer. The effect of this isomerism has been addressed in a fundamental contribution of Corey and Peterson, which is also one of the first applications of an auxiliary-based stereoselective Michael addition. The chiral lithium enolate 425 that was generated from the propionic ester 424 of phenylmenthol by deprotonation was assumed to adopt the enolate in fcr /is-configuration, in accordance with Ireland s model (cf Section 2.1). The reaction of the enolate with ( )- and (Z)-methyl crotonate led to the Michael products sy/i-426 and a f/-427, respectively. The Michael addition to ( )-crotonate was faster at low temperatures than that of the (Z)-diastereomer and provided higher chemical yields as well as syw-anti-selectivity and induced stereoselectivity. A closed, eight-membered transition state model 428 has been proposed that plausibly explains the opposite stereochemical outcome depending on the double-bond configuration of the Michael acceptor. As the rear side is shielded by the bulky 2-phenyl-2-propyl substituent, the attack of both croto-nates occurs at the Si-face of the enolate 425. Whereas Si-face of ( )-crotonate is selected for the addition of the enolate, the attack to (Z)-crotonate occurs predominantly from the e-face (Scheme 4.92) [206]. 

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